Two major goals of drug metabolism studies are 1) to identify toxic and active pathways of biotransformation, and 2) to modify either the therapeutic regimen of the drug or the structure of the drug itself in order to decrease toxic pathways and enhance desired pathways. Although the first goal has been attained with several drugs, the second goal has remained relatively elusive. The major emphasis of the proposed research will be an attempt to decrease known toxic metabolic pathways of some selected drugs by making minor structural modifications to alter the metabolism. Evidence has been presented that N-hydroxyamide metabolites of two widely used minor analgesics, p-hydroxyacetanilide (acetaminophen) and p-ethoxyacetanilide (phenacetin), mediate the hepatotoxicity and renal toxicity associated with their use. Therefore, methylation of the amide nitrogen should reduce the toxicity. Both N-methylacetaminophen and N-methylphenacetin will be tested for analgesic potency, methemoglobin formation, and toxicity to the liver and kidney in animals which serve as models for these toxicities in man. Additional studies will be undertaken to determine how the structural modification alters the metabolism and disposition of the two analogs. Salicylates are another class of widely used minor analgesics that can cause hepatic and renal damage in man. Animal models have been found for renal necrosis induced by salicylates, and preliminary evidence indicates that gentisic acid may be involved as a toxic metabolite. Therefore, analogs that are known to maintain salicylate activity and are substituted on the para position to the aromatic hydroxy group will be tested for toxicity in the animal model. Finally, alteration of metabolism by the structural modifications will be examined in the animal model. Procarbazine is a widely used anticancer agent that can cause toxic pulmonary reactions in man. Because the formation of toxic metabolites may be distinct for toxicity and anticancer activity, specific deuterium labeling will be used to examine possible isotope effects on the metabolism, anticancer activity, and toxicity of procarbazine.